Overview

MCTD is a systemic autoimmune rheumatic disease characterized by overlapping clinical features of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis, with rheumatoid arthritis with high titres of anti-U1 RNP antibodies. It typically affects women aged 20–40 years. Prevalence is estimated at 3.8 per 100,000; more common in females (F:M ~9:1). The disease course may evolve toward a predominance of one specific connective tissue disease phenotype over time.

Aetiology and Risk Factors

Aetiology

• Autoimmune dysregulation with production of high-titre anti-U1 RNP antibodies.
• Likely multifactorial: genetic predisposition, hormonal influence, and environmental triggers.
  

Risk Factors

• Female sex
• Age 20–40
• HLA-DR4 and HLA-DR2 alleles
• Family history of autoimmune disease.

Pathophysiology

• Trigger (e.g. infection or environmental antigen) leads to immune dysregulation.
• Overproduction of autoantibodies—especially anti-U1 RNP.
• Immune complexes deposit in target tissues → complement activation → inflammation.
• Chronic inflammation leads to fibrosis (especially pulmonary and dermal) and vascular damage (Raynaud’s).

Clinical Manifestations

Common Features mixture or overlap of the following:

• SLE
  • Photosensitive rash
• Systemic sclerosis
  • Pulmonary involvement (interstitial lung disease, pulmonary hypertension)
  • Raynaud’s phenomenon (often earliest sign)
  • Puffy/swollen hands (“sausage digits”)
  • Esophageal dysmotility (dysphagia, reflux)
  • Sclerodactyly and telangiectasia
• Rheumatoid arthritis
  • Arthralgia/arthritis (similar to RA, but non-erosive)
• Inflammatory myopathy
  • Proximal muscle weakness

Systemic Symptoms

• Fatigue, low-grade fever, weight loss
  

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Diagnosis

Diagnostic Criteria (Alarcón-Segovia, 1987 – widely used):

• Positive anti-U1 RNP antibodies (high titre)
• At least 3 of the following:
  • Raynaud’s phenomenon
  • Swollen hands
  • Synovitis
  • Myositis
  • Acrosclerosis

Investigations:

• ANA (usually positive, speckled pattern)
• Anti-U1 RNP (high titre)
• ESR/CRP (elevated)
• Creatine kinase (↑ if myositis)
• Pulmonary function tests (↓ DLCO in ILD or PH)
• HRCT chest (for ILD)
• ECG/Echo (screen for pulmonary hypertension)

Differential Diagnoses:

Treatment

• Individualized based on predominant features.

Mild disease (arthralgia, Raynaud’s):

• NSAIDs
• Hydroxychloroquine
• Nifedipine for Raynaud’s

Moderate-to-severe disease:

• Corticosteroids (e.g. prednisolone 0.5–1 mg/kg for myositis or ILD)
• DMARDs (methotrexate, azathioprine, mycophenolate)
• Rituximab (if refractory or ILD)
• PPI and prokinetics for esophageal symptoms

Pulmonary hypertension: endothelin receptor antagonists, sildenafil.

Complications and Prognosis

Complications

• Interstitial lung disease (most common and serious)
• Pulmonary hypertension (common)
• Secondary Sjögren’s syndrome

Prognosis

• 10-year survival >80% with treatment
• Pulmonary hypertension = major cause of mortality

Poor Prognostic Factors

• Severe ILD or pulmonary hypertension
• Cardiac involvement

High corticosteroid requirement.

References

1. Sharp GC et al. Autoantibodies to ribonucleoprotein in MCTD. Arthritis Rheum. 1972;15(6):629-35.
2. Alarcón-Segovia D et al. Mixed connective tissue disease: An overview. Rheum Dis Clin North Am. 2005;31(3):605-23.
3. Gunnarsson R et al. Mixed connective tissue disease criteria review. Scand J Rheumatol. 2005;34(1):48–53.
4. Greidinger EL. Advances in the understanding of MCTD. Curr Rheumatol Rep. 2015;17(7):39.
5. Burdt MA et al. Long-term outcomes of MCTD. Medicine (Baltimore). 1999;78(6):378-90.